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An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.

ABSTRACT: Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.

SUBMITTER: Weisser NE

PROVIDER: S-EPMC10011572 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.

Weisser Nina E NE Sanches Mario M Escobar-Cabrera Eric E O'Toole Jason J Whalen Elizabeth E Chan Peter W Y PWY Wickman Grant G Abraham Libin L Choi Kate K Harbourne Bryant B Samiotakis Antonios A Rojas Andrea Hernández AH Volkers Gesa G Wong Jodi J Atkinson Claire E CE Baardsnes Jason J Worrall Liam J LJ Browman Duncan D Smith Emma E EE Baichoo Priya P Cheng Chi Wing CW Guedia Joy J Kang Sohyeong S Mukhopadhyay Abhishek A Newhook Lisa L Ohrn Anders A Raghunatha Prajwal P Zago-Schmitt Matteo M Schrag Joseph D JD Smith Joel J Zwierzchowski Patricia P Scurll Joshua M JM Fung Vincent V Black Sonia S Strynadka Natalie C J NCJ Gold Michael R MR Presta Leonard G LG Ng Gordon G Dixit Surjit S

Nature communications 20230313 1

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combina ...[more]

PMID: 36914633

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Dataset Information

An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.

Publications

An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.

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